This is a K23 application for Dr. Babak Navi, a junior neurology investigator pursuing patient-oriented clinical research on the link between cancer and ischemic stroke. A K23 award will enable him to develop essential skills in three key career development areas: 1) epidemiology and biostatistics, 2) stroke pathophysiology and biomarker analysis, and 3) clinical trial design and implementation. Further training in these areas will allw Dr. Navi to achieve his long-term career goal of becoming an independent clinical investigator focused on reducing the incidence and burden of stroke in patients with cancer. To pursue his goal, Dr. Navi has recruited a primary mentor, Dr. Mitchell Elkind, a neurologist with expertise in stroke epidemiology, biomarkers, and clinical trials; and two co-mentors, Dr. Costantino Iadecola, a neurobiologist with expertise in stroke pathophysiology and biomarker discovery, and Dr. Lisa DeAngelis, a neurooncologist with expertise in clinical trials and neurological complications of cancer. Based on his own preliminary data and recent publications, Dr. Navi's central hypothesis is that solid tumor cancers independently increase the risk of ischemic stroke through cardio embolic mechanisms that arise from the hypercoagulable state produced by cancer and its treatments, and that the risks are greatest during chemotherapy and with advanced disease. Testing this hypothesis will address a fundamental knowledge gap about the risk and mechanisms of ischemic stroke in cancer patients. Until this knowledge gap is filled, our understanding of stroke pathophysiology will remain incomplete. Dr. Navi will pursue the following specific aims to test his hypothesis and gather data for prospective studies to further investigate stroke mechanisms and targeted stroke prevention strategies in cancer patients. Specific Aim 1 will test the hypothesis that active cancer of solid tumor origin increases the risk of ischemic stroke independent of potential confounders. This aim will be pursued using longitudinal data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) prospective cohort study to compare rates of stroke in patients with and without cancer. Specific Aim 2 will test the hypothesis that patients with cancer and ischemic stroke more often have cardio embolic mechanisms of stroke and higher markers of hypercoagulability than patients with stroke and no cancer. A prospective cohort of 55 patients with stroke and cancer, 55 with stroke and no cancer, and 55 with cancer and no stroke will be enrolled to compare markers of cardio embolism and hypercoagulability between groups using innovative RNA gene profiling techniques, coagulation function testing, and transcranial Doppler microemboli detection studies. Specific Aim 3 will test the hypothesis that solid tumor cancer increases the risk of ischemic stroke regardless of cancer type, and that the risk is highest in patients actively undergoing chemotherapy and in those with advanced, metastatic disease. This aim will be pursued using the Surveillance Epidemiology and End Results (SEER)-Medicare linked dataset to evaluate the effects of cancer type, stage, and treatments on stroke risk. The proposed work is significant because it will help conclusively establish cancer as an independent risk factor for ischemic stroke, which would newly identify millions of patients as facing an increased risk for stroke. This would be particularly relevant to public health as advances in cancer care lead to longer survival. Furthermore, this would significantly improve our understanding of stroke pathophysiology, and in the process would set the stage for future clinical trials of different stroke prevention strategies with the aim to reduce stroke morbidity ad mortality in cancer patients. The proposed work is innovative because it would lead to the widespread recognition and understanding of an underappreciated yet common risk factor for stroke, and also because it uses state-of-the-art and complementary investigative approaches to elucidate the mechanisms of ischemic stroke in this unique patient population.